Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient?

Nordness, Mina F.; Hamel, Stephanie A.; Godfrey, Caroline M.; Shi, Chanjuan; Johnson, Douglas B.; Goff, Laura Williams; O’Dell, Heather; Perri, Roman E.; Alexopoulos, Sophoclis P.

doi:10.1111/ajt.15617

Cited by 90 publications

(77 citation statements)

References 18 publications

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“…The main message from this table is that early‐stage disease that has responded to treatment may be considered for transplantation after 3 years with significant caution. It is also worth noting that the effects of checkpoint inhibition pretransplant may have unintended immunological consequences posttransplant 94 . Furthermore, the cancer control/remission through the use of checkpoint inhibitors may dissipate and lead to relapse when immunosuppression is introduced after transplantation.…”

Section: Methodsmentioning

confidence: 99%

Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion statement

Al‐Adra

Hammel²,

Roberts

et al. 2021

American Journal of Transplantation

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Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage‐specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer‐specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy.

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Section: Methodsmentioning

confidence: 99%

Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion statement

Al‐Adra

Hammel²,

Roberts

et al. 2021

American Journal of Transplantation

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“…64 However, another study reported the fatal liver necrosis of a patient who was treated with nivolumab for HCC and underwent LT 8 days after ICI discontinuation, indicating that this interval was probably too short. 65 As the duration of ICI activity, which is longer than the half-life of the agent, is not known, the time elapsing between treatment discontinuation and a safe transplant needs to be defined.…”

Section: Liver Transplant Recipientsmentioning

confidence: 99%

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

et al. 2020

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Immune checkpoint inhibitors (ICIs) improve clinical outcomes in patients suffering from different types of cancer. Liver toxicity is one of the immune-related adverse events associated with immunotherapy; although not common, its management is challenging as it is extremely heterogeneous in terms of presentation and severity. Differences in the development and evolution of ICI-related toxicity in healthy or cirrhotic livers have not yet been elucidated. Assessing causality is key to diagnosing ICI-induced liver toxicity; liver biopsies can assist not only in the differential diagnosis but also in assessing the severity of histological liver damage. The current classification of severity overestimates the grade of liver injury and needs to be revised to reflect the views of hepatologists. Spontaneous improvements in ICI-related liver toxicity have been reported, so corticosteroid therapy should probably be individualised not systematic. The reintroduction of ICIs in a patient with previous immune-mediated hepatitis may be possible, but the risk/benefit ratio should be considered, as the risk factors for hepatitis recurrence are currently unclear. The management of these patients, requiring a balance between efficacy, toxicity and specific treatments, necessitates multidisciplinary collaboration. The incidence of immune-related liver toxicity will continue to rise based on the increasing use of ICIs for most cancers, mandating improved understanding and management of this complication.

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“…This included 11 clinical trials (4 randomized and 7 nonrandomized) and 8 cohort studies (Table 1), 12 case series, and 32 case reports (supplemental online Table 3). Fifty of the articles described the use of immunotherapy agents in the setting of unresectable HCC [13, 14, 18, 29–75], 3 in the neoadjuvant setting [76–78], and 10 in the setting of LT [79–88], and they reported on 2,402 patients in total (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

The Role of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis of 2,402 Patients

Ziogas

Evangeliou²,

Giannis

et al. 2021

The Oncologist

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Background. Immune checkpoints inhibitors (ICIs) have emerged as a treatment option for several malignancies. Nivolumab, pembrolizumab, nivolumab plus ipilimumab, and atezolizumab plus bevacizumab have been approved for the management of advanced-stage hepatocellular carcinoma (HCC). We aimed to systematically review the literature and summarize the characteristics and outcomes of patients with HCC treated with ICIs. Methods. A systematic literature search of PubMed, the Cochrane Library, and ClinicalTrials.gov was performed according to the PRISMA statement (end of search date: November 7, 2020). Quality of evidence assessment was also performed. Results. Sixty-three articles including 2,402 patients were analyzed, 2,376 of whom received ICIs for unresectable HCC. Response to ICIs could be evaluated in 2,116 patients; the overall objective response rate (ORR) and disease control rate (DCR) were 22.7% and 60.7%, respectively, and the mean overall survival (OS) was 15.8 months. The ORR, DCR, and OS for nivolumab (n = 846) were 19.7%, 51.1%, and 18.7 months, respectively; for pembrolizumab (n = 435) they were 20.7%, 64.6% and 13.3 months, respectively. The combination of atezolizumab/bevacizumab (n = 460) demonstrated an ORR and DCR of 30% and 77%, respectively. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence); fatal graft rejection was reported in 40.0% (n = 6/15) and mortality in 80.0% (n = 12/15). Conclusion. ICIs are safe and effective against unresectable HCC, but caution is warranted regarding their use in the LT setting because of the high graft rejection rate. The Oncologist 2020;25:1-14 Implications for Practice: This systematic review pooled the outcomes from studies reporting on the use of immune checkpoint inhibitors (ICIs) for the management of 2,402 patients with advanced-stage hepatocellular carcinoma (HCC), 2,376 of whom had unresectable HCC. The objective response rate and disease control rate were 22.7% and 60.7%, respectively, and the mean overall survival was 15.8 months. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence). Six of these patients experienced graft rejection (40.0%).

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Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient?

Cited by 90 publications

References 18 publications

Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion statement

Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion statement

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

The Role of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis of 2,402 Patients

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